Synthesis of steroids

ABSTRACT

This invention relates to novel methods of synthesizing 3 Alpha ,7 Alpha -dihydroxy-5 Beta -cholanic acid, and to novel intermediates therefor.

United States Patent [191 Saitzman ,Tune 241, 11975 SYNTHESIS OF STEROIDS [75] 1nventor: William H. Saltzman, New

Rochelle, NY.

[73] Assignee: Intellectual Property Development Corporation, New Rochelle, NY.

[22] Filed: Nov. 26, 1973 [21] App]. No.: 419,014

Related US. Application Data [63] Continuation of Ser. No. 307,060, Nov. 16, 1972,

Pat. NO. 3,833,260.

[52] US. Cl. 260/397.1 [51] Int. (11. C071 9/96 [58] Field of Search /Machine Searched Steroids [56] References Cited OTHER PUBLICATIONS Levine et al., J.A.C.S., V01. 82, pp. 3391-3395,

Primary ExaminerElbert L. Roberts 5 7 ABSTRACT This invention relates to novel methods of synthesizing 3a,7a-dihydroxy-5B-cholanic acid, and to novel intermediates therefor.

8 Claims, No Drawings SYNTHESIS OF STEROIDS This application is a continuation in part application of my prior filed, copending application Ser. No. 307060, filed Nov. 16, 1972 now U.S. Pat. No.

This invention relates to and has for its object the synthesis of 3a,7oz-dihydroxy-SB-cholanic acid and novel intermediates therefor. The final compounds of this invention are known and have been found to possess useful biological properties.

A novel method has been discovered for the production of 304,7oz-dihydroxy-SB-cholanic acid, which entails a number of steps beginning with 3a,7a,l2atrihydroxy-SB-cholanic acid or analogs thereof as starting material. More particularly, this invention involves the method of producing 304,7a-dihydroxy-SB-cholanic acid directly from 3a,7a,1Za-trihydroxy-SB-cholanic acid or analogs thereof and is more fully and clearly illustrated by the following chemical equations wherein R, Z, Y and X are as defined in the respective formulae below:

the presence of a palladium over charcoal catalyst, a procedure which is well known in the art.

The preferred acyl or acyloxy radicals of this invention are those of hydrocarbon carboxylic acids of twelve carbon atoms or less and include such acids as the lower alkanoic acids, the lower alkenoic acids, the cycloalkanoic acids, the cycloalkenoic acids, the aryl carboxylic acids, and other like hydrocarbon carboxylic acids.

The preferred alkyl radicals of this invention are those of six or less carbon atoms and may be characterized by the term, lower alkyl. Thus, as employed herein, lower alkyl is meant to include such moieties as methyl, ethyl, propyl, t.-butyl, pentyl and the like.

The final products of this invention are useful in the medical treatment of various disorders, for example, the treatment of hypertriglyceridemia, and may be employed for such purposes in the dosage forms and amounts as may be determined to be effective by the skilled worker practicing the invention.

The invention may be further illustrated by the folln the first step of the process of this invention, the compounds of formula A may be treated to obtain the compounds of formula B. More particularly, it has been found that it is possible to obtain the ll-ene compounds (compounds B) from the 3,7,12-triol compounds (Compounds A) by treating Compounds A with a strong dehydration agent. The dehydration agents which have been found to be suitable in the practice of this invention include such dehydration agents as, methane sulfonyl chloride, thionyl chloride or methyl chlorosulfite in the presence of an organic base, for example, pyridine. By the practice of this invention it has been found possible to obtain the desired 1 l-ene compounds (compounds B) which may then be further treated in accordance with the instant invention to yield the desired 3a,7a-diol final products of this invention.

The final 3a,7a-diol compounds (Compounds C) are then obtained by the hydrogenation of the l l-ene compounds (Compounds B), for example, by catalytic hydrogenation, such as by hydrogenation in acetic acid in lowing examples:

EXAMPLE l EXAMPLE 2 Methyl 3oz,7a-diacetoxy-5,8-chol-l l-en-3a,7ozdiol-24- oic acid The procedure of Example 1 is followed except that an equivalent amount of methyl chlorosulfite is substituted for methanesulfonyl chloride, to yield the methyl 3a,7a-diacetoxy-5,8-chol-l 1-en-3a,7a-diol-24-oic acid.

EXAMPLE 3 Methyl 3a,7a-diacetoxy-5,8-chol-1 l-en-3a,7ozdiol-24- oic acid To a solution of methyl 3a,7oz-diacetoxy-5B-cholan- 3a,7a, l2a-triol-24-oic acid in pyridine was added thionyl chloride and the mixture held at room temperature overnight. The reaction mixture was then poured into iced water and the resultant precipitate collected,

Q agent is:thionylchloride.

washed and dried. The resultant material was then recrystallized from methanol to yield methyl 301,704- diacetoxy-SB-chol-l l-en-3a,7a-diol-24-oic acid.

EXAMPLE 4 Methyl 3a,7a-diacetoxy 5/3-cholan-3a, 7a-diol-24-oic acid Methyl 3a,7a-di'acetoxy-5B-chol-l l-en-3a,7 oZ-diol- 24-oic acid was subjected to hydrogenation in acetic acid in the presence of palladium on charcoal and the resultant product was recrystallized from methanol to yield methyl-3 01,7 o -diacetoxy- B-cholan-3 a,7a-diol- 24-oic acid.

EXAMPLE 5 3(1,7a-Dihydroxy-SB-Cholanic Acid Methyl 3a,7oz-diacetoxy-5/3-cholan-3a,7a-diol-24- oic acid was refluxed in a 5 percent alcoholic solution of potassium hydroxide for four hours. Upon recrystallization of the resultant product from ethyl acetate there was obtained 304,7a-dihydroxy-SB-cholanic acid.

In the formulae set forth herein and the Claims appended hereto, X and Z may be hydrogen or acyl, while R may be hydrogen or lower alkyl, all without departing from the satisfactory practice of the instant inven-' tron.

The invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

l. The method of producing compounds of the formula wherein each Z is hydrogen or acyl; and R is hydrogen or lower alkyl; with a dehydrating agent selected from the group consisting of methane sulfonyl chloride, methyl chlorosulfite, and thionyl chloride.

2.=- The method of claim 1 wherein the dehydrating 3. The method ofclaim 1 wherein the dehydrating agent is methane sulfonyl chloride.

4. The method of claim 1, wherein the dehydrating agent is methylchlorosulfite.

, 4 5. The method of producing acorripound of the formula I wherein Z and R are as defined'in claim 1; which comprises;

a. Dehydrating'a compound of the formula:

wherein Z and R are as defined in claim l, by treatment with a dehydrating agent selected from the group consisting of thionyl chloride, methane sulfonyl chloride and methyl chlorosulfite, to yield the l l-ene compound of the formula:

wherein Z and R are as defined in claim 13 and b. Hydrogenating said 1 l-ene compound-to yield the desired final product.

6. The method of claim 5, wherein in step a., the dehydrating agent is thionyl chloride.-

7. The method of claim 5, wherein instep a., the dehydrating'agent" is methane sulfonyl chloride.

8. The method of claim 5, wherein' in step a., the dehydrating ag'ent is methyl chlorosulfite. 

1. THE METHOD OF PRODUCING COMPOUNDS OF THE FORMULA
 2. The method of claim 1 wherein the dehydrating agent is thionyl chloride.
 3. The method of claim 1 wherein the dehydrating agent is methane sulfonyl chloride.
 4. The method of claim 1, wherein the dehydrating agent is metHylchlorosulfite.
 5. The method of producing a compound of the formula
 6. The method of claim 5, wherein in step a., the dehydrating agent is thionyl chloride.
 7. The method of claim 5, wherein in step a., the dehydrating agent is methane sulfonyl chloride.
 8. The method of claim 5, wherein in step a., the dehydrating agent is methyl chlorosulfite. 